Preeclampsia and gestational hypertension are associated with an increased risk of adverse prenatal outcomes. Altered immune-mediated inflammatory events in the placenta contribute to the pathogenesis of these hypertensive diseases of pregnancy. The complement system, a component of the innate immune system is a series of over 30 proteins that combats infection and removes immune complexes as well as ischemic, necrotic and apoptotic cells. An intact complement system is important in pregnancy. Novel research from marine models of the antiphospholipid antibody syndrome and spontaneous fetal loss has shown that complement activation in the deciduas is a major effectors for both intra-uterine fetal loss and intra-uterine growth restriction. We have translated these important findings into a study in human pregnancy, the Denver Complement Study. This study - the first to examine the role of the complement pathways in early pregnancy - made the important original discovery that elevated levels of complement activation fragments in a single plasma sample drawn at less than 20 weeks'gestation are significantly associated with an increased risk of gestational hypertension and preeclampsia later in pregnancy. In this proposed study we propose to move this research forward to address the important question of the natural history of complement activation fragments measured longitudinally in pregnancy and their links with gestational hypertension-preeclampsia. These questions have not been previously addressed in a prospectively studied pregnant cohort. We have developed the following specific aim: To determine the association between complement activation fragments measured at multiple time points in gestation with subsequent development of hypertensive diseases of pregnancy in a longitudinal study design. We will recruit a cohort of 600 ethnically and racially diverse pregnant women and follow them prospectively during pregnancy with sequential blood samples for the complement activation fragments. This research will identify a new inflammatory marker of hypertensive diseases of pregnancy. If our hypothesis is proven there may be therapeutic implications as several complement inhibitors are now available that target various components of the complement system thus modifying the effects of the inflammatory cascade. PUBLIC HEALTH RELEVANCE: Preeclampsia and gestational hypertension are associated with an increased risk of adverse prenatal outcomes. This project has the potential to identify new complement biomarkers for hypertensive diseases of pregnancy. The results of the study may ultimately hasten the development of new therapeutic interventions for this adverse pregnancy outcome.